Recent studies have found that the receptor for advanced glycation endproducts (RAGE) plays an important role in the pathogenesis of pulmonary fibrosis and acute lung injury. In contrast to other tissues where RAGE expression is low and increases with disease, RAGE is highly expressed in the normal lung and its expression decreases in response to pulmonary injury. We found that RAGE protects against fibrosis in the lung, which led us to investigate the physiologic role of RAGE. Pulmonary RAGE localizes to the basement membrane side of type I alveolar epithelial cells. We found that RAGE has a very high affinity for components of the basement membrane including: collagen I, collagen IV, and laminin. We also found that RAGE loses this affinity in the presence of its ligand, AGEs (advanced glycation endproducts). This led us to study the effect of chronic exposure to excess RAGE ligand and what role it might have on pulmonary RAGE expression and subsequent predisposition to pulmonary disease. Notably, uncontrolled diabetes with sustained hyperglycemia leads to the overproduction of the RAGE ligand, AGE. This ligand contributes to many systemic complications that occur in diabetic patients including vascular disease, and nephropathy. However, few studies have examined the effects of diabetes and AGEs in lung disease. Elevated levels of the RAGE ligand, AGEs, in diabetics may increase their risks of pulmonary complications. We hypothesize that high levels of RAGE ligands, such as occurs in diabetics, will disrupt normal pulmonary epithelial RAGE/basement membrane interactions. This will lead to enhanced de-epithelialization, impaired re-epithelialization and lead to an augmented fibrotic response. PUBLIC HEALTH RELEVANCE: Idiopathic pulmonary fibrosis is a disease that causes scaring of the lungs. The cause of this disease is not known, but there are about 40 new cases of this disease for every 100.000 people each year. There is no treatment available for patients with this disease and most patients will die from their disease three to five years after being diagnosed. A better understanding of how this disease develops will allow us to develop better treatment strategies for patients with this terrible disease. We have found that a protein called the receptor for advanced glycation endproducts is present in high levels in the lung and that it plays an important role in the progression of pulmonary fibrosis. This grant application will determine how molecules that signal through this receptor may contribute to pulmonary fibrosis and how blocking signaling through this receptor may offer a viable treatment option for patients with this relentlessly progressive disease.